High dietary intake of Vitamin K2 reduces risk of Peripheral Arterial Disease: Study

Preventing PAD, rather than treating it, is the first line of management considered by doctors.

Vitamin K1 (phylloquinone) and Vitamin K2 (menaquinones) are the two active form of Vitamin K. Derived from different sources, Vitamin K1 (phylloquinone), is present in green, leafy vegetables and certain vegetable oils [1] whereas Vitamin K2 (menaquinones) occurs in animal products such as meat, eggs, and fermented foods like cheese and curd [2].

An increase in the daily intake of vitamin K1 and vitamin K2 is known to reduce cardiovascular disease and peripheral arterial disease (PAD) risk. One of the main mechanisms is by reducing vascular calcification. It further prevents arterial calcification and arterial stiffening by its activating matrix GLA protein (MGP), which inhibits the deposits of calcium on the walls.

It was noted in previous research, that only a high intake of Vitamin K2 was associated with a decreased risk of coronary heart disease (CHD) risk (3,4,5). Lower incidences of vascular calcification (6,7) and CHD (8,9) were also accounted for. Justifying this, in a study, W J Beulens et al (3) had concluded that this may be due to different effects of vitamin K1 (phylloquinone) and vitamin K 2 (menaquinone, MK) on the coronary artery.

In another randomized, placebo-controlled trial, (7) researchers studied the effect of menaquinone-7 supplementation on the progression of Coronary (CAC) artery calcification. They concluded that MK-7 supplementation slows down the progression of CAC in patients with CAD.

Though these above-mentioned studies had been done previously, the association of vitamin K intake with PAD had not been investigated thoroughly.

With this background, In 2016, Linda E.T. Vissers et al (10) at the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands carried out a study to explore possible clinical applicability for the relationship between low vitamin K status and PAD to investigate the relationship between dietary intake of phylloquinone and menaquinones and risk of PAD. Furthermore, they went on to examine this association in the general population and the effect of modification through cardiovascular risk factors such as sex, hypertension, and diabetes.

Findings were published in Atherosclerosis (Elsevier).

The study population was selected from 2 separate cohort bases by age-stratified randomization. The MORGEN-EPIC cohort consisted of 22,654 adults aged 20-65 years. The Prospect-EPIC cohort included 17,357 women aged 49-70 years, providing a total study population of 40,011 persons. Written informed consent was taken before study inclusion. The study complied with the Declaration of Helsinki and was approved by the institutional review board of the University Medical Centre Utrecht.

Participants filled out a general questionnaire containing questions on demographics and risk factors for chronic diseases. A physical examination was performed for baseline parameters.

Both the systolic and diastolic blood pressure measurements were performed twice on the right arm with the participant in the supine position using a Boso Oscillomat (Prospect) or on the left arm using a random zero sphygomanometer (MORGEN). Finally, the mean of the duplicate measurements was taken.

Among physical parameters, height and weight were measured and body mass index (BMI) was calculated. Waist and hip circumference were measured.

Vitamin K contents of 260 food items were collected and tabulated to estimate the intake of phylloquinone and menaquinones. Daily dietary intake was obtained through a validated food frequency questionnaire (FFQ) containing questions on the usual frequency of consumption of 79 main food items.

The occurrence of PAD was obtained by linkage to national registries from 1993 with complete follow up until January 1, 2008.

Additionally, the researchers calculated HRs for each 50 mg increment of energy-adjusted phylloquinone intake and each 10 mg increment of energy-adjusted menaquinones intake. Researchers also explored the presence of interaction of phylloquinone or menaquinones with sex, hypertension, and diabetes, as effect modifiers in the model.

Data analysis was done with Multivariate Cox regression which was used to estimate adjusted hazard ratio&#39;s for the association. Results were considered statistically significant at two-sided p <=0.05.

In the study, the authors documented an average follow-up of 12.1 years, SD 2.1 years, with 489 cases of PAD.

Results brought forth the following facts.

· For both phylloquinone and menaquinones in relation to PAD, an interaction was found with hypertension (p < 0.001) and diabetes (p < 0.001).

• Although a lower risk of PAD with higher menaquinone intake was suggested among participants with diabetes, the associations were not statistically significant.

• In the larger stratum of hypertensive participants, menaquinone intake was significantly associated with a lower risk of PAD after final multivariate adjustment for age, sex, cardiovascular risk factors and dietary factors

• Among participants without hypertension, no significant association was observed

• Effect estimates in the hypertensive stratum suggested a higher risk of PAD with higher phylloquinone intake, but the association did not reach significance.

• In participants without hypertension, high phylloquinone intake was not significantly associated with PAD risk in the final multivariate model.

• After stratification for hypertension, the interaction term for diabetes was no longer statistically significant. No interaction with sex was found for PAD.

• Sensitivity analysis with adjustment for prevalent CVD and excluding participants with prevalent CVD did not materially change the results, nor did exclusion of the first two years of follow-up.

· A reduced PAD risk was associated with a high intake of menaquinones, especially in hypertensive participants. Phylloquinone intake was not associated with PAD risk.

· Menaquinones are transported by triacylglycerol-rich lipoprotein, and also by low-density lipoprotein which transports it to extra-hepatic tissues such as the vascular wall [3]. Once in the vessel wall, menaquinones also have a longer half-time than phylloquinone, thus leading to a larger extra-hepatic efficacy of menaquinones.

· People with hypertension or diabetes usually already have some form of atherosclerosis and this pre-existent higher degree of atherosclerosis may increase the effect of vitamin K.

· Vitamin K not only prevents the calcification of a vessel bed but can also reduce calcification that is already present.

· A high menaquinone intake may be associated with a reduced risk of PAD in participants with diabetes as well, though no statistically significant.

1. C. Bolton-Smith, R.J. Price, S.T. Fenton, D.J. Harrington, M.J. Shearer, Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods, Br. J. Nutr. 83 (2000) 389e399.

2. L.J. Schurgers, C. Vermeer, Determination of phylloquinone, and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations, Haemostasis 30 (2000) 298e307.

3. J.W. Beulens, M.L. Bots, F. Atsma, et al., High dietary menaquinone intake is associated with reduced coronary calcification, Atherosclerosis 203 (2009) 489e493.

4. J.M. Geleijnse, C. Vermeer, D.E. Grobbee, et al., Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study, J. Nutr. 134 (2004) 3100e3105.

5. G.C. Gast, N.M. de Roos, I. Sluijs, et al., A high menaquinone intake reduces the incidence of coronary heart disease, Nutr. Metab. Cardiovasc Dis. 19 (2009) 504e510.

6. J.W. Beulens, M.L. Bots, F. Atsma, et al., High dietary menaquinone intake is associated with reduced coronary calcification, Atherosclerosis 203 (2009) 489e493.

7. Rennenberg RJ, van Varik BJ, Schurgers LJ, Hamulyak K, Ten CH, Leiner T, Vermeer C, de Leeuw PW, Kroon AA. Chronic coumarin treatment is associated with increased intracoronary arterial calcification in humans. Blood. 2010; 115:5121-5123

8. J.M. Geleijnse, C. Vermeer, D.E. Grobbee, et al., Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study, J. Nutr. 134 (2004) 3100e3105

9. G.C. Gast, N.M. de Roos, I. Sluijs, et al., A high menaquinone intake reduces the incidence of coronary heart disease, Nutr. Metab. Cardiovasc Dis. 19 (2009) 504e510.

10.Vissers LET, Dalmeijer GW, Boer JMA, Verschuren WMM, van der Schouw YT, Beulens JWJ, The relationship between vitamin K and peripheral arterial disease, Atherosclerosis (2016), DOI: 10.1016/j.atherosclerosis.2016.07.915.